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The study by Cramer et al. follows in a long series of epidemiological reports studying the effects of statins on the incidence of Alzheimer disease. Most of the studies observe lower incidence of Alzheimer disease among statin users, although a small number of studies do not see an effect of statins. The current study reports a strong reduction in incident Alzheimer disease among statin users, supporting a putative beneficial effect of statins for Alzheimer disease. The major question now is whether prospective trials will produce results consistent or discordant with the epidemiological studies of statins. Four prospective studies have been published addressing the effects of statins on dementia or cognitive decline, with two small trials focused on cognitive loss showing modest benefit and two large trials focused on cardiovascular disease but using cognitive add-on structures showing no benefit. The LEADe study presented at the AAN meeting reported no benefit for atorvastatin in delaying progression of AD, although post-hoc testing suggests a potential benefit for some subgroups. Results from a prospective trial of simvastatin are due imminently. Thus, the weight of the current data indicates overwhelmingly positive results for epidemiological studies, but possible negative studies for prospective clinical trials. This discrepancy might reflect either of two possibilities. One possibility is that the epidemiological studies reflect a design structure that is not achieved in prospective clinical trials. For instance, the duration of exposure to statins might be longer than in prospective clinical trials, and the medication might be acting earlier in the disease course. The other possibility is that the positive results from the epidemiological studies reflect a bias in the datasets that lead to a false positive result. Distinguishing between these two possibilities is exceedingly difficult.

Although quite a lot of epidemiological studies have been published over the recent years, they have failed to provide a definitive answer as to whether statins protect against dementia. All we can conclude is that there is a reasonable likelihood that statin use and reduced dementia risk go together. Given the variability among the studies—in study design and outcome—it has to be assumed that we are still missing essential information.

There has been a general trend to move from therapeutic intervention to early intervention or prevention.
This is appropriate, and to be realistic, we have to acknowledge that nothing that is in the pipeline today, statins or others, appears to be terribly effective. For statins this likely breaks down to the relative simple formula that effectiveness equals the product of long-term treatment (during mild AD or before) and high statin dosage. Moreover, not all statins are expected to be equally potent. It is a pity that none of the studies published thus far had access to data that would allow us to address this point. One hope is that the prospective clinical trials on statins and AD prevention will provide more clear-cut answers. The other hope is that as time progresses and conversion to AD continues, the populations, which are continued to be monitored in the epidemiological studies, will also produce these data.